Neuroanatomical alterations in Alzheimer disease. Alzheimer disease (AD) dementia affects 1 in 10 American families, and costs more than 90 billion dollars a year. Genetic and neuropathological evidence highlight a pathogenic role for Abeta, but the exact mechanism of how Abeta alters neural system function is uncertain. Nonetheless, Abeta is a key therapeutic target, and clinical trials using anti-Abeta approaches are underway. In the last 5 years of this grant we developed in vivo multiphoton microscopy techniques to image Abeta deposits in living transgenic mouse models, and discovered that anti-Abeta immunotherapy can clear existing plaques. Our goal is to test the hypothesis that Abeta induces synaptic failure, and to examine the consequences in both mice and humans of anti-Abeta immunotherapy. Aim 1 examines hypotheses linking plaques with alterations in axons. Whether axonal dystrophies precede or follow plaque formation will be examined by imaging neuronal processes and plaques in young APP X YFP mice, then re-imaging them at later times. Transport of molecules and organelles near and distant from plaques will be examined in vivo using photoactivatable GFP constructs, introduced by AAV and Lentiviral vectors. Aim 2 builds on the observation that postsynaptic elements, including dendritic spines, are lost near plaques. We will examine whether dendritic spines are less stable near plaques by imaging spine turnover. We will also determine if dendritic segments near plaques are functionally less active using a new genetically encoded reporter of synaptic activation, a 3'-5'UTR CAMKIIalpha/EGFP chimeric molecule. Passive immunization against Abeta, and application of oligomeric Abeta, will be used to test the hypothesis that Abeta is directly responsible for these axonal and dendritic pathologies. The third aim proposes parallel studies of pre and postsynaptic structures in human AD autopsy material, including studies of autopsy tissue from individuals who had participated in the first immunotherapy trial, AN1792. Case reports show that plaque clearance occurs after vaccination. We have now organized a collaborative group of neuropathologists from multiple sites to examine systematically human tissue in which antibody mediated clearance of plaques has occurred. We believe that the questions posed in this application have high clinical relevance, and the severity and prevalence of the disease add urgency to these studies.